Mitochondrial oxidative phosphorylation deficiency is accompanied by various down-stream, adaptive responses which play a key role in the varied phenotypes observed when mitochondrial dysfunction occurs. These responses are often accompanied by the induction of genes involved in defense mechanisms against oxidative stress. Among these responses, metallothioneins (MTs) has been identified to be responsive to mitochondrial dysfunction. MTs, which are expressed in four different isoforms, are small, cysteine rich, metal binding proteins that have been associated with a protective effect in cells under numerous diseased and stressed states. Their diverse functionality and protective roles can be ascribed to their three basic abilities or primary functions which are metal homeostasis, heavy metal detoxification and free radical scavenging. The involvement of MTs with numerous cellular processes, organelles and cells has received much attention while notice of their involvement with the function of mitochondria has been lacking. It is believed that MTs promote the survival of mitochondrial dysfunctional cells by acting as highly efficient reducing elements against the damaging properties of reactive oxygen species (ROS) and by limiting apoptosis. In addition to their role in mitochondrial disease, convincing evidence exist, albeit with conflicting results, of its involvement in some key functions of the mitochondrion, including redox modulation, metal homeostasis and enzyme and transcription factor regulation.

Obesity continues to rise as an alarming global epidemic. System level mechanisms, diagnostics, and therapeutics are sorely needed so as to identify at risk individuals and design appropriate population scale interventions. The present study evaluated the protective role of metallothioneins (MTs) against obesity and high-fat diet-induced effects such as insulin resistance in both male and female MT-1+2 knockout and MT-3 knockout mice. As the metabolome is closest to the functional phenotype, changes in metabolite levels were also evaluated, and the direct or indirect involvement of MTs in metabolism examined. MT-1+2−, MT-3 knockout, and wild-type mice were given a high-fat diet for 2 months. Variation in body weight gain, tissue weight, and response to oral glucose tolerance test and insulin tolerance test were determined and compared to mice that received the control diet. Effect of the high-fat diet on the knockout mice were investigated on the metabolome level in specific tissues using metabolomics. Both knockout mice strains were more susceptible to high-fat diet-induced effects, such as weight gain and moderate insulin resistance, with the MT-3 knockout mice most susceptible. Brain tissue of the knockout mice showed most metabolic variation and pointed to possible impairment of mitochondrial function. The protective effect of MTs against high-fat diet and obesity-induced effects such as insulin resistance was evident from our observations. The putative role MTs play in mitochondrial function is possibly the main contributor to the lack of these effects in wild-type mice. Considering the expression profiles of the MT isoforms and similarity in brain metabolic variation in the knockout strains, it appears that they promote mitochondrial function in the hypothalamus, thereby limiting weight gain and insulin resistance. Furthermore, metabolomics research in preclinical models of obesity and in the clinic is warranted in the near future.